This application is a response the call, PAR-13-023 Exploratory/Developmental Projects in Translational Research. The goal is to demonstrate the preliminary efficacy of using adeno-associated viral vector (AAV) - mediated expression of soluble FMS-related tyrosine kinase 1 (sFLT1), also called vascular endothelial growth factor (VEGF) receptor-1, for the treatment of brain arteriovenous malformations (bAVM). Brain AVM is an important cause of intracranial hemorrhage (ICH). Available therapies have potentially high morbidity, and due to excessive risk, about 20% of patients are currently not offered treatment. There is also considerable controversy over whether ruptured bAVMs should be treated using invasive modalities. Excessive VEGF expression seems to be a fundamental part of the bAVM pathology. Compelling evidence show interruption of VEGF signaling could be a therapeutic strategy. There is a single-case report of bevacizumab (Avastin, an anti-VEGF monoclonal antibody) treatment resulting in marked improvement in the symptoms of a bAVM patient who had developed headaches and hemiparesis after stereotactic radiosurgery. Importantly, in an animal model of the bAVM phenotype, we showed that anti-VEGF therapy with bevacizumab reduced the number of abnormal vessels. However, antibody therapy has many drawbacks, including concerns over inducing hemorrhage and the need for prolonged periods of intermittent intravenous (i.e.) infusions. Soluble FLT (sFLT1) binds to and neutralizes VEGF in the tissue, thus reducing its downstream signaling through membrane-bound VEGFRs. Soluble FLT1 in an AAV construct packaged in AAV serotype 2 capsid (AAV2) inhibited choroid neovascularization in a non-human primate model, which has led to a Phase Me clinical trial for macular degeneration (NCT01024998). However, AAV2 does not cross the blood-brain barrier (BBB). We wish to deliver the vector through a non-invasive manner, intravenously or intra-arterially, using serotype 9 to package the vector (AAV9), because AAV9 enters the brain parenchyma much more effectively. The overarching goal of the project is to test if intravascular delivery of AAV-sFLT packaged in AAV9 capsid will prevent progression of or reverse the abnormal vascular phenotype in our bAVM phenotype models. Once the sFLT therapeutic efficacy is proved, we will couple the AAV9 vector to a tetracycline-response and central nervous system (CNS)-targeted promoter (e.g., promoter of glial fibrillary acidic protein), which allow spatial an temporal control of gene expression. Key preliminary data obtained from this study will provide the basis for a successful U01 cooperative agreement application, which will develop an innovative strategy to implement therapy for the human disease. Ultimately, this study will result in preclinical developments that will allow us to apply for an IND and early- phase clinical trials